tbuckley/cabot-search huggingface dataset:
Associations and relative risks of pulmonary hypertension and lung diseases in individuals with methamphetamine use disorder
Authors: S.C. Fang, C.Y. Huang, S.M. Huang, Y.J. Shao
Journal: Pulmonology (2023)

Methamphetamine causes considerable short- and long-term adverse health effects. Our aim was to assess the effects of methamphetamine use on pulmonary hypertension and lung diseases at the population level.This population-based retrospective study used data from the Taiwan National Health Insurance Research Database between 2000 and 2018 that included 18,118 individuals with methamphetamine use disorder (MUD) and 90,590 matched participants of the same age and sex without substance use disorder as the non-exposed group. A conditional logistic regression model was used to estimate associations of methamphetamine use with pulmonary hypertension and lung diseases such as lung abscess, empyema, pneumonia, emphysema, pleurisy, pneumothorax, or pulmonary hemorrhage. Incidence rate ratios (IRRs) of pulmonary hypertension and hospitalization due to lung diseases were determined between the methamphetamine group and non-methamphetamine group using negative binomial regression models.During an 8-year observation period, 32 (0.2%) individuals with MUD and 66 (0.1%) non-methamphetamine participants suffered from pulmonary hypertension, and 2652 (14.6%) individuals with MUD and 6157 (6.8%) non-methamphetamine participants suffered from lung diseases. After adjusting for demographic characteristics and comorbidities, individuals with MUD were 1.78 times (95% confidence interval (CI) = 1.07-2.95) more likely to have pulmonary hypertension and 1.98 times (95% CI = 1.88-2.08) more likely to have a lung disease, especially emphysema, lung abscess, and pneumonia in descending order. Furthermore, compared to the non-methamphetamine group, the methamphetamine group was associated with higher risks of hospitalization caused by pulmonary hypertension and lung diseases. The respective IRRs were 2.79 and 1.67. Individuals with polysubstance use disorder were associated with higher risks of empyema, lung abscess, and pneumonia compared to individuals with MUD alone, with respective adjusted odds ratios of 2.96, 2.21, and 1.67. However, pulmonary hypertension and emphysema did not differ significantly between MUD individuals with or without polysubstance use disorder.Individuals with MUD were associated with higher risks of pulmonary hypertension and lung diseases. Clinicians need to ensure that a methamphetamine exposure history is obtained as part of the workup for these pulmonary diseases and provide timely management for this contributing factor.
Asthma hospitalizations: A call for a national strategy to fight health inequities
Authors: R.J. Vieira, B. Sousa-Pinto, A.M. Pereira, C.R. Cordeiro, C.C. Loureiro, F. Regateiro, L. Taborda-Barata, J. Bousquet, J. Fonseca
Journal: Pulmonology (2023)

T a g g e d H 1 Asthma hospitalizations: A call for a national strategy to fight health inequitiesT a g g e d E n d T a g g e d P Health inequities are differences in the health status or the distribution of health resources between different population groups, arising from the social conditions in which people are born, grow, live, work and age. 1 Such inequities have high social and economic costs for individuals and societies worldwide. 1Lower socioeconomic status is among the risk factors associated with worse health outcomes and leads to a higher rate of potentially preventable hospital admissions. 2 This may reflect regional differences in access to healthcare (e.g., delays in access to secondary care) and primary care quality, which have been significantly associated with avoidable emergency admissions. [3]4][5] This is especially important for chronic conditions in which proper management may avoid exacerbations, 6,7 as is the case of asthma. 8 There is evidence that people with asthma living in deprived areas may have impaired asthma outcomes across all stages of patient care, leading to a higher rate of hospitalizations and risk of asthma-related deaths. 9,10As health inequities have remained insufficiently studied in Portugal, in particular regarding access to care, 11 we assessed whether such inequities may occur in Portugal as well, by studying the association between the region of residence and the frequency of asthma hospitalizations.T a g g e d E n d T a g g e d P In mainland Portugal, between 2011 and 2015, there were 9161 asthma hospitalizations in adults, according to data from the national administrative database containing all hospitalizations in public hospitals from mainland Portugal (ICD-9-CM code 493.x).Therefore, there was an average of 92.6 hospital admissions per 100,000 inhabitants and 13.5 hospital admissions per 1000 inhabitants with asthma.Mainland Portugal is composed of 18 districts (Fig. 1A).The districts with the highest rates of asthma hospital admissions per 100,000 inhabitants were Coimbra (213.2 hospitalizations per 100,000 inhabitants), Castelo Branco (160.6/100,000), Viseu (155.4/100,000) and Guarda (140.9/100,000), all of which are in the center region of Portugal and are (except for Coimbra) inland districts.Taking into account the prevalence data from the most recent Portuguese epidemiological survey carried out in 2010 12 (Fig. 1B),
Predicting risk on cardiovascular or cerebrovascular disease based on a physical activity cohort: Results from APAC study
Authors: Juan Zhao, Ye Yu, Xiaolan Zhu, Yuling Xie, Songwei Ai, H. Immo Lehmann, Xuan Deng, Feifei Hu, Guoping Li, Yong Zhou, Junjie Xiao
Journal: MedComm (2023)

Abstract Commonly used prediction models have been primarily constructed without taking physical activity into account. Using the Kailuan physical activity cohorts from Asymptomatic Polyvascular Abnormalities in Community (APAC) study, we developed a 9‐year cardiovascular or cerebrovascular disease (CVD) risk prediction equation. Participants in this study were included from APAC cohort, which included 5440 participants from the Kailuan cohort in China. Cox proportional hazard regression model was applied to construct sex‐specific risk prediction equations for the physical activity cohort (PA equation). Proposed equations were compared with the 10‐year risk prediction model, which is developed for atherosclerotic cardiovascular disease risk in Chinese cohorts (China‐PAR equation). C statistics of PA equations were 0.755 (95% confidence interval, 0.750–0.758) for men and 0.801 (95% confidence interval, 0.790–0.813) for women. The estimated area under the receiver operating characteristic curves in the validation set shows that the PA equations perform as good as the China‐PAR. From calibration among four categories of predicted risks, the predicted risk rates by PA equations were almost identical to the Kaplan–Meier observed rates. Therefore, our developed sex‐specific PA equations have effective performance for predicting CVD for physically active cohorts in the physical activity cohort in Kailuan.
Digital therapeutics from bench to bedside
Authors: Changwon Wang, Chungkeun Lee, Hangsik Shin
Journal: npj Digital Medicine (2023)

Abstract As a new therapeutic technique based on digital technology, the commercialization and clinical application of digital therapeutics (DTx) are increasing, and the demand for expansion to new clinical fields is remarkably high. However, the use of DTx as a general medical component is still ambiguous, and this ambiguity may be owing to a lack of consensus on a definition, in addition to insufficiencies in research and development, clinical trials, standardization of regulatory frameworks, and technological maturity. In this study, we conduct an in-depth investigation and analysis of definitions, clinical trials, commercial products, and the regulatory status related to DTx using published literature, ClinicalTrials.gov, and web pages of regulatory and private organizations in several countries. Subsequently, we suggest the necessity and considerations for international agreements on the definition and characteristics of DTx, focusing on the commercialization characteristics. In addition, we discuss the status and considerations of clinical research, key technology factors, and the direction of regulatory developments. In conclusion, for the successful settlement of DTx, real-world evidence-based validation should be strengthened by establishing a cooperative system between researchers, manufacturers, and governments, and there should be effective technologies and regulatory systems for overcoming engagement barriers of DTx.
Patient-centric synthetic data generation, no reason to risk re-identification in biomedical data analysis
Authors: Morgan Guillaudeux, Olivia Rousseau, Julien Petot, Zineb Bennis, Charles-Axel Dein, Thomas Goronflot, Nicolas Vince, Sophie Limou, Matilde Karakachoff, Matthieu Wargny, Pierre-Antoine Gourraud
Journal: npj Digital Medicine (2023)

While nearly all computational methods operate on pseudonymized personal data, re-identification remains a risk. With personal health data, this re-identification risk may be considered a double-crossing of patients' trust. Herein, we present a new method to generate synthetic data of individual granularity while holding on to patients' privacy. Developed for sensitive biomedical data, the method is patient-centric as it uses a local model to generate random new synthetic data, called an "avatar data", for each initial sensitive individual. This method, compared with 2 other synthetic data generation techniques (Synthpop, CT-GAN), is applied to real health data with a clinical trial and a cancer observational study to evaluate the protection it provides while retaining the original statistical information. Compared to Synthpop and CT-GAN, the Avatar method shows a similar level of signal maintenance while allowing to compute additional privacy metrics. In the light of distance-based privacy metrics, each individual produces an avatar simulation that is on average indistinguishable from 12 other generated avatar simulations for the clinical trial and 24 for the observational study. Data transformation using the Avatar method both preserves, the evaluation of the treatment's effectiveness with similar hazard ratios for the clinical trial (original HR = 0.49 [95% CI, 0.39-0.63] vs. avatar HR = 0.40 [95% CI, 0.31-0.52]) and the classification properties for the observational study (original AUC = 99.46 (s.e. 0.25) vs. avatar AUC = 99.84 (s.e. 0.12)). Once validated by privacy metrics, anonymous synthetic data enable the creation of value from sensitive pseudonymized data analyses by tackling the risk of a privacy breach.
Antitumor activity of aumolertinib, a third-generation EGFR tyrosine kinase inhibitor, in non-small-cell lung cancer harboring uncommon EGFR mutations
Authors: Chen Shi, Cong Zhang, Zhiwen Fu, Jinmei Liu, Yuanfeng Zhou, Bao Cheng, Cong Wang, Shijun Li, Yu Zhang
Journal: Acta Pharmaceutica Sinica B (2023)

Uncommon epidermal growth factor receptor (EGFR) mutations account for 10%–20% of all EGFR mutations in non-small-cell lung cancer (NSCLC). The uncommon EGFR-mutated NSCLC is associated with poor clinical outcomes and generally achieved unsatisfactory effects to the current therapies using standard EGFR-tyrosine kinase inhibitors (TKIs), including afatinib and osimertinib. Therefore, it is necessary to develop more novel EGFR-TKIs to treat uncommon EGFR-mutated NSCLC. Aumolertinib is a third-generation EGFR-TKI approved in China for treating advanced NSCLC with common EGFR mutations. However, it remains unclear whether aumolertinib is effective in uncommon EGFR-mutated NSCLC. In this work, the in vitro anticancer activity of aumolertinib was investigated in engineered Ba/F3 cells and patient-derived cells bearing diverse uncommon EGFR mutations. Aumolertinib was shown to be more potent in inhibiting the viability of various uncommon EGFR-mutated cell lines than those with wild-type EGFR. And in vivo, aumolertinib could also significantly inhibit tumor growth in two mouse allograft models (V769-D770insASV and L861Q mutations) and a patient-derived xenografts model (H773-V774insNPH mutation). Importantly, aumolertinib exerts responses against tumors in advanced NSCLC patients with uncommon EGFR mutations. These results suggest that aumolertinib has the potential as a promising therapeutic candidate for the treatment of uncommon EGFR-mutated NSCLC.
Hepatic COX1 loss leads to impaired autophagic flux and exacerbates nonalcoholic steatohepatitis
Authors: Qian Yu, Chang Li, Qinghui Niu, Jigang Wang, Zhaodi Che, Ke Lei, He Ren, Boyi Ma, Yixing Ren, Pingping Luo, Zhuming Fan, Huan Zhang, Zhaohui Liu, George L. Tipoe, Jia Xiao
Journal: Acta Pharmaceutica Sinica B (2023)

The mechanisms underlying autophagic defects in nonalcoholic steatohepatitis (NASH) remain largely unknown. We aimed to elucidate the roles of hepatic cyclooxygenase 1 (COX1) in autophagy and the pathogenesis of diet-induced steatohepatitis in mice. Human nonalcoholic fatty liver disease (NAFLD) liver samples were used to examine the protein expression of COX1 and the level of autophagy. Cox1Δhepa mice and their wildtype littermates were generated and fed with 3 different NASH models. We found that hepatic COX1 expression was increased in patients with NASH and diet-induced NASH mice models accompanied by impaired autophagy. COX1 was required for basal autophagy in hepatocytes and liver specific COX1 deletion exacerbated steatohepatitis by inhibiting autophagy. Mechanistically, COX1 directly interacted with WD repeat domain, phosphoinositide interacting 2 (WIPI2), which was crucial for autophagosome maturation. Adeno-associated virus (AAV)-mediated rescue of WIPI2 reversed the impaired autophagic flux and improved NASH phenotypes in Cox1Δhepa mice, indicating that COX1 deletion-mediated steatohepatitis was partially dependent on WIPI2-mediated autophagy. In conclusion, we demonstrated a novel role of COX1 in hepatic autophagy that protected against NASH by interacting with WIPI2. Targeting the COX1-WIPI2 axis may be a novel therapeutic strategy for NASH.
Airway hyperresponsiveness reflects corticosteroid-sensitive mast cell involvement across asthma phenotypes
Authors: Morten Hvidtfeldt, Asger Sverrild, Alexis Pulga, Laurits Frøssing, Alexander Silberbrandt, Morten Hostrup, Martin Thomassen, Caroline Sanden, Carl Magnus Clausson, Premkumar Siddhuraj, Daisy Bornesund, Juan Jose Nieto-Fontarigo, Lena Uller, Jonas Erjefält, Celeste Porsbjerg
Journal: Journal of Allergy and Clinical Immunology (2023)
An optimized SpCas9 high-fidelity variant for direct protein delivery
Authors: Eleonora Pedrazzoli, Andrea Bianchi, Alessandro Umbach, Simone Amistadi, Mégane Brusson, Giacomo Frati, Matteo Ciciani, Kalina Aleksandra Badowska, Daniele Arosio, Annarita Miccio, Anna Cereseto, Antonio Casini
Journal: Molecular Therapy (2023)

Electroporation of the Cas9 ribonucleoprotein (RNP) complex offers the advantage of preventing off-target cleavages and potential immune responses produced by long-term expression of the nuclease. Nevertheless, the majority of engineered high-fidelity Streptococcus pyogenes Cas9 (SpCas9) variants are less active than the wild-type enzyme and are not compatible with RNP delivery. Building on our previous studies on evoCas9, we developed a high-fidelity SpCas9 variant suitable for RNP delivery. The editing efficacy and precision of the recombinant high-fidelity Cas9 (rCas9HF), characterized by the K526D substitution, was compared with the R691A mutant (HiFi Cas9), which is currently the only available high-fidelity Cas9 that can be used as an RNP. The comparative analysis was extended to gene substitution experiments where the two high fidelities were used in combination with a DNA donor template, generating different ratios of non-homologous end joining (NHEJ) versus homology-directed repair (HDR) for precise editing. The analyses revealed a heterogeneous efficacy and precision indicating different targeting capabilities between the two variants throughout the genome. The development of rCas9HF, characterized by an editing profile diverse from the currently used HiFi Cas9 in RNP electroporation, increases the genome editing solutions for the highest precision and efficient applications. Electroporation of the Cas9 ribonucleoprotein (RNP) complex offers the advantage of preventing off-target cleavages and potential immune responses produced by long-term expression of the nuclease. Nevertheless, the majority of engineered high-fidelity Streptococcus pyogenes Cas9 (SpCas9) variants are less active than the wild-type enzyme and are not compatible with RNP delivery. Building on our previous studies on evoCas9, we developed a high-fidelity SpCas9 variant suitable for RNP delivery. The editing efficacy and precision of the recombinant high-fidelity Cas9 (rCas9HF), characterized by the K526D substitution, was compared with the R691A mutant (HiFi Cas9), which is currently the only available high-fidelity Cas9 that can be used as an RNP. The comparative analysis was extended to gene substitution experiments where the two high fidelities were used in combination with a DNA donor template, generating different ratios of non-homologous end joining (NHEJ) versus homology-directed repair (HDR) for precise editing. The analyses revealed a heterogeneous efficacy and precision indicating different targeting capabilities between the two variants throughout the genome. The development of rCas9HF, characterized by an editing profile diverse from the currently used HiFi Cas9 in RNP electroporation, increases the genome editing solutions for the highest precision and efficient applications.
Prognostic factors for satellitosis or in-transit metastasis in cutaneous squamous cell carcinoma: A multicentric cohort study
Authors: Ignasi Marti-Marti, Sebastian Podlipnik, Javier Cañueto, Carla Ferrándiz-Pulido, Gustavo Deza, Onofre Sanmartín, Ane Jaka, Sonia Beà-Ardèbol, Rafael Botella-Estrada, Pedro Redondo, Lucía Turrión-Merino, Verónica Ruiz-Salas, Emili Masferrer, Mireia Yébenes, Júlia-María Sánchez-Schmidt, Inés Gracia-Darder, Arcadi Altemir-Vidal, Rafael S. Aguayo-Ortiz, Sara Becerril, Domingo Bodet-Castillo, Lorena Leal, Maria José Fuente, Oscar Muñoz Moreno-Arrones, Carlos Abril-Pérez, Alejandra Tomás-Velázquez, Alejandra Sandoval-Clavijo, Agustí Toll
Journal: Journal of the American Academy of Dermatology (2023)
Pain of local anesthetic injection of lidocaine during subsequent stages of Mohs micrographic surgery: A multicenter prospective cohort study
Authors: McKenzie A. Dirr, Rachel E. Christensen, Noor Anvery, Umer Nadir, Matthew Schaeffer, Emir Veledar, Kira Minkis, Michael Nodzenski, Adam Whittington, Joaquin C. Brieva, Rebecca Tung, Emily Poon, Murad Alam
Journal: Journal of the American Academy of Dermatology (2023)
Peri-Partum respiratory management in neuro-muscular disorders (IT-NEUMA-Pregn study): A proposal by an italian panel and a call for an international collaboration
Authors: F. Racca, Y. Longhitano, C. Zanza, G. Draisci, P.A. Stoia, E. Gollo, M. Maio, C. Grattarola, M. Astuto, R. Vaschetto, V.A.M. Sansone, G. Conti, C. Gregoretti
Journal: Pulmonology (2023)
A biomaterial-based therapy for lower limb ischemia using Sr/Si bioactive hydrogel that inhibits skeletal muscle necrosis and enhances angiogenesis
Authors: Ye Yuan, Zhaowenbin Zhang, Fandi Mo, Chen Yang, Yiren Jiao, Enci Wang, Yuchong Zhang, Peng Lin, Chengkai Hu, Weiguo Fu, Jiang Chang, Lixin Wang
Journal: Bioactive Materials (2023)

Muscle necrosis and angiogenesis are two major challenges in the treatment of lower-limb ischemic diseases. In this study, a triple-functional Sr/Si-containing bioceramic/alginate composite hydrogel with simultaneous bioactivity in enhancing angiogenesis, regulating inflammation, and inhibiting muscle necrosis was designed to treat lower-limb ischemic diseases. In particular, sodium alginate, calcium silicate and strontium carbonate were used to prepare injectable hydrogels, which was gelled within 10 min. More importantly, this composite hydrogel sustainedly releases bioactive Sr
Navigating and adapting care integrating immunotherapy, antiangiogenic therapy, and combinations in patients with advanced renal cell carcinoma
Authors: Brian I Rini, James Brugarolas, Michael B Atkins
Journal: Journal for ImmunoTherapy of Cancer (2023)

Advanced renal cell carcinoma is a biologically heterogeneous disease with multiple treatment options that largely involve immunotherapy and/or anti-angiogenic therapies. The choice of initial and subsequent therapy depends on both clinical and biological considerations. Here, we describe the application of recent data to clinical practice.
Accumulation of T-cell-suppressive PD-L1<sup>high</sup>extracellular vesicles is associated with GvHD and might impact GvL efficacy
Authors: Rebecca Baur, Franziska Karl, Romy Böttcher-Loschinski, Andrej Stoll, Simon Völkl, Andreas Gießl, Cindy Flamann, Heiko Bruns, Ursula Schlötzer-Schrehardt, Martin Böttcher, Denis M Schewe, Thomas Fischer, Regina Jitschin, Andreas Mackensen, Dimitrios Mougiakakos
Journal: Journal for ImmunoTherapy of Cancer (2023)

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents the only curative treatment option for a number of hemato-oncological disorders. In fact, allo-HSCT is considered as one of the most successful immunotherapies as its clinical efficacy is based on the donor T-cells’ capacity to control residual disease. This process is known as the graft-versus-leukemia (GvL) reaction. However, alloreactive T-cells can also recognize the host as foreign and trigger a systemic potentially life-threatening inflammatory disorder termed graft-versus-host disease (GvHD). A better understanding of the underlying mechanisms that lead to GvHD or disease relapse could help us to improve efficacy and safety of allo-HSCT. In recent years, extracellular vesicles (EVs) have emerged as critical components of intercellular crosstalk. Cancer-associated EVs that express the immune checkpoint molecule programmed death-ligand 1 (PD-L1) can suppress T-cell responses and thus contribute to immune escape. At the same time, it has been observed that inflammation triggers PD-L1 expression as part of a negative feedback network. Here, we investigated whether circulating EVs following allo-HSCT express PD-L1 and tested their efficacy to suppress the ability of (autologous) T-cells to effectively target AML blasts. Finally, we assessed the link between PD-L1 levels on EVs to (T-)cell reconstitution, GvHD, and disease relapse. We were able to detect PD-L1 + EVs that reached a peak PD-L1 expression at 6 weeks post allo-HSCT. Development of acute GvHD was linked to the emergence of PD-L1 high EVs following allo-HSCT. Moreover, PD-L1 levels correlated positively with GvHD grade and declined (only) on successful therapeutic intervention. T-cell-inhibitory capacity was higher in PD-L1 high EVs as compared with their PD-L1 low counterparts and could be antagonized using PD-L1/PD-1 blocking antibodies. Abundance of T-cell-suppressive PD-L1 high EVs appears to also impact GvL efficacy as patients were at higher risk for relapse. Finally, patients of PD-L1 high cohort displayed a reduced overall survival.Taken together, we show that PD-L1-expressing EVs are present following allo-HSCT. PD-L1 levels on EVs correlate with their ability to suppress T-cells and the occurrence of GvHD. The latter observation may indicate a negative feedback mechanism to control inflammatory (GvHD) activity. This intrinsic immunosuppression could subsequently promote disease relapse.